July 1966
LOCAL , ! W E S T H E T I C ACYL
1,2-DIETHYL-3-HYDROXY.METHYLPYH..IZOLIDIXES
493
New Local Anesthetics.' I. Esters of 1,2-Diethyl-3-hydroxymethylpyrazolidine MILTONJ. I~ORSET Colkge of Pharmacy, University of Kentucky, Lexington, Kentucky Received September 17, 1965
A new alcohol, lJ2-dieth~l-3-hydroxymethylpyrazo1idine, has beeii prepared in two steps from IJ-diethylhydrazine and diethyl maleate. Transesterification of this alcohol with several methyl esters afforded eleven new esters embodying the pyrazolidine ring system. The hydrochloride salts of thebe esters possess local anesthetic activity.
Since the introduction of procaine by EinhornJz nierized to a considerable extent. Treatment of the basic esters V with HC1 gave the hydrochloride salt several thousand ester-type local anesthetics have derivatives (see Table 11). been synthesized. A great number of these arose by variation of the amino alcohol portion of the m ~ l e c u l e . ~ I n the present study ester-type compounds have been prepared in which the customary amino alcohol has been replaced by an alcohol incorporating an -?\'-Nlinkage and in this series of compounds the -S-Klinkage is part of a pyrazolidine ring system. These esters bear structural resemblances to procaine, piperocaine, and other synthetic local anesthetics. Local Anesthetic Activity.-The compounds preThe alcohol embodying the pyrazolidine ring was pared were evaluated according to the procedure of constructed in the following way. Treatment of 1,2Block and co-workers using earthworms of genus diethylhydrazine (I) with diethyl maleate (11) gave a Lumbricus.j Each compound was tested a t four or good yield of 1,2-diethyl-5-ethoxycarbonyl-3-pyrazoli- five concentrations (0.015-0.8%) and five worms were dirione (111). The latter compound may be visualized used for each concentration. Straight line plots were as arising by an addition of the hydrazine to the a,Pobtained when the response time (min) was plotted unsaturated ester, followed by closure to the fiveagainst per cent concentration on log scale. The membered ring with elimination of a molecule of ethrelative potencies were calculated using 10 niin as the anol. A somewhat similar reaction, that of hydrazine mean response time. The results are summarized in with ethyl niethacrylate to give 4-methyl-3-pyrazolidiTable 11. The most potent compound was assigned a none has been r e p ~ r t e d . The ~ structure of I11 is suprelative anesthetic potency of 100%. By comparison, ported by elemental analysis and its infrared spectrum the standard piperocaine hydrochloride had a relative (see Experimental Section). Reduction of the amido anesthetic potency of 17%. ester I11 by lithium aluniinuni hydride gave the alcohol, The structure-activity relationship results obtained 1,2-diethy1-3-hydroxyniethylpyrazolidirie (IV) . The latin this work parallel findings previously made for ter was converted to a picrate derivative upon treatbenzoate esters.6 Thus, introduction of a p-amino ment with picric acid. substituent results in a compound of higher potency than the unsubstituted benzoate, Although the p (CJ&NH), methoxy-substituted derivative was less active than the I p-amino-substituted derivative, the corresponding ethLiAIH; oxy derivative was more active (see Table 11). The t introduction of an o-fluor0 substituent gives a comCHC0,C2H, pound less active than the p-amino derivative, also in I11 IICH CO, C,H agreement with previous work.' Soteworthy are + + - C H ~ O H compounds 4 and 6 of Table 11; the former is apI1 proxiniately 6 times as potent as piperocaine hydroc,H,~-~c~H, chloride and the latter is about 3 times as potent.
c~H,~-Ac,H~
IV
Reaction of IV under transesterification conditions with eleven different methyl esters afforded the basic esters (V) containing the pyrazolidine ring system (see Table I ) . Yields in the latter reaction mere good with the possible except'ion of the reaction involving methyl p-aminobenzoate. This methyl ester poly(1) For recent reviews on local anesthetics see: (a) s. Wiedling and C. Tegner in "Progress in Medicinal Chemistry," Voi. 3, G. P. Ellis a n d G. B. N-est, Ed., Butterworth Inc., Washington, D. C . , 1963, p 332; (b) S.Oldham, M / g . Chemist, 36, No. 12, 50 (1964). (2) A. Einhorn and E. Uhlfelder, Ann., 971, 131 (1909). (3) T. P. Carney in "Medicinal Chemistry," C. A I . Suter, E d . , John b'iley and Sons, Inc., New York, N. Y., 1951, p 280. (4) T. Lieser and K . Kemmner, Chem. Ber., 84, 4 (1951).
Experimental Section* Most of the required methyl ehters were obtained from commercial sources. Methyl p-ethoxybenzoate wit5 prepared by the published procedure.g ( 5 ) B. P. Block, D. J. Potts, and R . S. H. Finney, J . P h a r m . Pharmacal. S u p p l . , 16, 85T (1964).
( 6 ) Reference l a , p 354. (7) G. A . Olah, A. E. Pavlath, J. A . Olah, a n d F. Herr, J . Org. Chem., %a, 879 (1957). (8) hlelting points were determined with t h e Fisher-Johns apparatus and are uncorrected. Infrared spectra n e r e recorded on a Beckman I R 8 spectrophotometer using NaCl optics. Microanalyses were performed by Dr. K u r t Eder, Geneva, Saitzerland. (9) R . West, S. Ornstein, D. AlcKee, and R. Layzer, J . A m . Chem. Soc., 74, 3960 (1952).
49.2
3113, " C
I1
104-105 115.3-119.3 1G5.-166 126.5-1'2S t29-1:30 134- 1:33 105. 5-107 128-129 128 141- 11"
7 76 7 111) 7.71 4 72 7 66 7 .!I4
x , :s
- .,., I .*I*>
7.71: 7.71
.\lctliyl ~ ~ - ( ~ ~ - I ) u t y l : ~jl,eirzo:ite i ~ i i i i o was prepared hy t d t l i t ioii of sufficient ethereal diazomethaiie til 7.72 g (0.04 mole) of p-( T I t,iityl:tiniito)beii~oic, acid in 50 1111of ether t o give :i yellow color a1iic:h persi,.ted. The clear solutioti which resulted was evaporated t o dryness in Z ' U C ~ L O . 0 1 1 rec from aqueous ethanol, 7.4 g ( obtained, mp 107-109", lit.1omp 104-105". \Iethj-l p-cyclohexyloxybeiizoate was prepared by atlditioii of sufticierit et>hereal diazomet,hane to 8.8 g (0.04 mole) of p loliexyloxybenzoit. acid in 1-50 ml of ether ti) give :t yellow color which persisted. The ethereal .wlutioii as washed oiice with water :tiid dried (;\IgSOa). The speiit drying ageiil WLC filtered : i n t i the ether was distilled. Distillatioii of the residue atforded 8.14 g (87%) of the ester, bp 127" (0.55 mm), nZ%
1,2-l)iethyl-3-hydroxymethylpyrazolidine.---A siJlntioti of XJ.7 g (0.228 riicile) of ~,2-diethyl-5-ethoxy~ar~)oii~l-3-p!-~)~i~itli)li(~
i i i GO riil I J f iiiihydr~u:,ether was added dropwise with ptirritig to :I holut i o t i of 13.2 g (0.X4S mole) of LiAlH, iii 130 ml of atihydrous PI her. .Ifier cwmplet ioii of the :itl(lition the r e d ion mist w e \\-:IS rrflusetl for 13 hr. 1)ecoinpositioi~ of t tie romples was cffec,ted b j - 40(,.; aqueou; KOII with ic*e-l)ntli miling. 'rhc ctlier 1:iyer L T ~ Rseparated tilid the iniorgaiiir salts \wrc exi.r:tcd c d 1 wice ivith 100-rid porticjii- of ether. The corrihincd (+hc!r cst ri1c.t- \vert> dric,tl (IIgSO,). After removal of t h e spent, dryitig : i ~ e t i ~the , ether \ v w tli~t~llrtl o i i :I w t i e r 1)ath. Thr residue w a h tlthtilletl aiid yieltied 25.8 g (71.6cy ) of it viicous, colorlehs liquid, bp 46' (0.24 m m ) , n% 1.4700, AriiL'I32.95-3.15 (II-l,oiidcd OH), 2.78 p (free O H ) . r l n n l . Cnlcd fi)r (.;8111J2(): C, 60.7%; 11, 11.47; S . 17.70. 1..5421. .Inal. (Mid for C~,JT,&~: 71.77; 11, 7.74. F o ~ ~ i d : Fourid: C', 60.62; [I, 11.54: S, 17.i5. t:tllitie I)icmte derivative was prepared :tiid r( c, 71.78; II, 7.82. 1,2-Diethyl-5-ethoxycarbonyl-3-pyrazolidinone.---~~1~ :L soltitiriii IJf 46.5 g (0.528 mole) of l,S-dieth~-lhydraaiiie" in 25 nil . l d . Cdcd for CI,HZiS,O~;: C, 43.41 : I I , >.4(i; S , lS.lIS. of :haolute ethaiiol !vas added a >olutioti of 86.0 g ( 0 . 5 0 0 mole) I'Oulid: (:, 43.~58;11, 5.3!>;N; 18.05. Esters of l,X-Diethyl-3-hydroxymethylpyrazolidine. General of diet.hy1 maleate in 65 ml of tlwolute ethanol dropwise, with Method.--To a solution of 1,2-dietIiyl-3-h~droxymethylpyrasolistirring mid ice-bath cooling. After 5tirring a t room temperature dine (0.05 mole) i n 60 nil of dry heptane was added a 1-niiii3 overnight, the reaction mixture wiis refluxed on the steam bath piere of freshly (:lit scidiuiii. The resulting solution wts healed for 5.25 hr. The ethaiiol was removed in ZJCLCUO and the residue 011 ail oil bath uiitil the sodium dissolved. The mixture was w:is distilled atitl amounted to 95.7 g (89,5yc)of a colorless oil, cooled, a11 appropriate methyl ester (0.05 mole) was added, h p 94' (0.05 mm), n z o1.4646, ~ A C r x c 1 3 3 79 (wter C=O), 5.98 q atid the reaction mixturc was refluxed under a Dean-Stark tube (amide C=O). riiitil t,he theoretical amount of methanol had separated (10-40 .lnal. Calcd for C:oI~18K20,3: (1, .X.O3; IT, 8 . 6 ; S , 13.08. k'ourid: C, 55.91; IT, 8.51; ?;, 12.94. hr). Xfter washing twice r i t h 5-ml portions of water, the hept m e solution was dried (IzIgS04). The spent drying agent \vas filtered and t h e heptaiie was removed by distillatioil :it :itmo.-pheric pressure. The residue was then distilled uiicler :10) .I. I
